2011 Research Grant Awards

The following departmental faculty were awarded competitive and non-competitive research grants during calendar year 2011.

Richard Moon, MD, Medical Director of the Center for Hyperbaric Medicine and Environmental Physiology, and Dawn Kernagis, received a two-year $254,897 grant from the Office of Naval Research entitled “Identification of Blood Biomarkers of Decompression Stress (DCS) through Genome-Wide Expression Profiling”. Dawn is currently a graduate student at Duke University working with Dr. Moon on her Ph.D. thesis work focused on identifying blood biomarkers of decompression stress in divers and investigating how genetics may influence individual susceptibility to decompression sickness.

Decompression sickness (DCS) is a physical manifestation of decompression stress (DS), defined as the physiologic response to dissolved gas coming out of solution into the venous circulation as a body moves from a high pressure to low pressure environment, such as surfacing from a dive. At present, the only measure of DS is the direct manifestation of symptoms (DCS). Biochemical measures of an individual’s response to venous bubbling could provide a mechanism to monitor subclinical DS and lead to safer and more time effective decompression profiles. Identifying blood biochemical markers for DS could also provide insight into the molecular interactions with gas emboli, allowing for the development of preventive, adjunctive or non-recompressive therapies for DCS. However, no specific biomarkers of DS or specific biochemical predictors of DCS have been described. Additionally, there are no data available describing interaction of physiological pathways in the pathology of DS or DCS. Genome-wide expression profiling allows for comprehensive exploration of gene patterns or aberrant gene expression associated with disease and biological processes. The goals of this project are to identify and validate global gene expression patterns characteristic of DS, evaluate potential blood biomarkers of DS, and determine the role of genetic variation in differential DS response and susceptibility to DCS.

Perioperative myocardial injury (PMI) due to ischemia/reperfusion (I/R) remains a major cause of cardiovascular morbidity and mortality following cardiac surgery. The molecular and cellular mechanisms associated with PMI have not yet been satisfactorily clarified and need further investigation. NF-kB mediated pro-inflammatory responses triggered by cardiopulmonary bypass (CPB), myocardial I/R, and neutrophil transmigration during cardiac surgery play key roles in PMI. Therefore, inhibition of myocardial inflammation in general, and NF-kB activation in particular, could be beneficial for patients undergoing cardiac surgery. This study will assess important parameters of the pharmacological action of ANXA1sp; explore its mechanism of action; and set the stage for its thorough preclinical evaluation that is required for first-in-man cardioprotective applications.

Dr. W. Daniel Tracey of the Division of Basic Sciences and Director of the Molecular Genetics of Pain Signaling Laboratory received a 4-year $1,193,200 NIH R01 Grant from the National Institute of General Medical Sciences (NIGMS) entitled “A Genome-Wide Analysis of Nociception Molecules, from Express to Function”.

A thorough understanding of the molecular machinery that operates in nociceptive sensory neurons will lead to greater understanding of the protective molecular mechanisms of acute pain. To identify nociception molecules, we previously carried out a genetic screen for nociception defective mutants using the fruitfly Drosophila melanogaster. This led to our discovery of the painless gene, which shows enriched expression in nociceptive sensory neurons and is required for acute nociception. The painless gene, as well as a related gene named dTRPA1, encode homologues of TRPA1. Human mutations in TRPA1 mutations lead to familial episodic pain syndrome (FEPS) and TRPA1 is highly expressed in nociceptor neurons. We have identified pickpocket as a critical regulator of mechanical nociception which is specifically expressed in Drosophila nociceptors. This research project will identify other genes expressed in nociceptor neurons of Drosophila and to test the functional requirement of those genes in nociception. In the short term, these studies will provide critical insight into molecular and cellular mechanisms of nociception using a high throughput approach that is made possible using Drosophila. In the long term, these studies may eventually allow for the identification of evolutionarily conserved mechanisms that contribute to human nociception.

Jeffrey Taekman MD, Director of the Human Simulation and Patient Safety Center), Noa Segall PhD, and Melanie Wright PhD, in collaboration with Virtual Heroes / Applied Research Associates were awarded a 18-month $1.8 million contract from the U.S. Army Medical Research and Materiel Command (USAMRMC) (of which $400,442 will be coming straight to Duke University), for a project entitled “U.S. Army Pre-Deployment Anesthesiology Training Simulator”.

Caregivers operating in austere field environments with multiple critically ill and wounded patients, different Standard Operating Procedures (SOPs), and unfamiliar equipment must possess extraordinary levels of proficiency. These caregivers face limited staffing and a potential for mass casualty situations. The Forward Surgical Team (FST), the Mobile Army Surgical Hospital (MASH), and the Combat Support Hospital (CSH) must function effectively upon arrival in theater. Anesthesia providers must arrive ready to work productively in an established team. Thus, a major element of success for these organizations is the speed with which they integrate new Anesthesia providers into the team. Military field treatment protocols may be unfamiliar to a clinician who has not previously deployed. Pre-deployment training offers an opportunity to familiarize with equipment, SOPs, and the deployed environment. As an augmentation to existing pre-deployment training methods for Anesthesia providers, this project proposes constructing a fully-functional, gametechnology- based, virtual simulator to train Anesthesia providers and accelerate cognitive proficiency on the critical skills related to Moderate Sedation and RSI.

Joseph P. Mathew, MD, MHS c, Professor of Anesthesiology and Chief of the Division of Cardiothoracic Anesthesia and Critical Care Medicine received a 2-year $431,750 NIH Exploratory/Developmental Research Grant Award (R21) from the National Heart, Lung, & Blood Institute (NHLBI) entitled “Cortical Beta-amyloid Levels and Neurocognitive Performance after Cardiac Surgery”. In this research proposal, the team, which includes Dr. Murali Doraiswamy from Psychiatry and Dr. Ed Coleman from Radiology, plans to determine the relationship between global cortical betaamyloid deposition and postoperative cognitive dysfunction (POCD). Additional goals are to assess the regional patterns of amyloid deposition in patients with POCD and to assess the effect of APOE4 genotype on amyloid burden. Defining the role of amyloid burden in POCD using molecular imaging markers that reveal the earliest neuronal changes may generate new mechanistic insights into this common complication after cardiac surgery.

Luke James, MD, Assistant Professor in the Division of Otolaryngology, Head, Neck/Neuroanesthesiology was awarded an Investigator Initiated Study Grant from Baxter Healthcare Corporation totaling $129,525 for his study entitled “Gammagard Improves Outcomes in Murine Models of Closed Head Injury”. The basis for the proposal is that IVIG administered after closed cranial injury in mice will improve functional short- and long-term neurological outcomes through neuroprotective mechanisms.

Traumatic brain injury is a leading cause of death and disability in industrialized societies. Annually within the U.S. there are approximately 1.5 million head injuries, resulting in approximately 300,000 hospital admissions, 52,000 deaths and nearly 80,000 cases of severe long-term disability. At present, treatment is largely supportive. The current proposal will build on the idea that immunomodulation can decrease the degree of neuronal injury after traumatic injury.

Melanie C. Wright, PhD, Assistant Professor of Anesthesiology and Human Factors Specialist in the Human Simulation and Patient Safety Center, received a 2-year $418,798 NIH Exploratory / Developmental Research Grant Award (R21) from the National Library of Medicine (NLM) entitled “Toward Intelligent Display of Health Data: A Qualitative Study of Use Patterns”. This project proposes a unique approach to eliciting provider descriptions of the relative importance of specific health data in the context of their own data use activities. These descriptions will be analyzed to identify emerging themes related to information seeking and principles that can be applied to the organization and prioritization of clinical health data. This proposal has significant implications for the design of electronic health records to support faster information access and to ensure that critical information is not missed. This proposal also includes effort from Drs. Noa Segall, Jeffrey Taekman, Eugene Moretti, and Rebecca Schroeder.

John J. Freiberger, MD, MPH, Assistant Professor of Anesthesiology and Member of the Center for Hyperbaric Medicine and Environmental Physiology received a 3-year $995,792 award from the Department of the Navy for his project entitled “Hypercapnia: Cognitive Effects and Monitoring”.

Carbon dioxide (CO2) retention is an operational risk to the exercising diver. Elevated PCO2 can cause sudden and unexpected cognitive impairment as well as increase the risk of O2 toxicity. The effect of elevated PCO2 on a working diver at varying levels of narcosis is untested and the Navy has stated a need for an algorithm to compute “equivalent narcotic depth” on the basis of inspired breathing gas partial pressures. A system that can detect elevated inspired PCO2 as well as provide an estimate of arterial PCO2 with appropriate alarms during a working dive that would allow the diver to take corrective action.

In order to meet the Navy’s request and need, this project will simulate the conditions of a working, helmet diver by using “head out” immersed subjects. Cognitive performance will be assessed using an auditory or visual N-back test that delivers a series of stimuli to the subject consisting of an auditory tone or a sequence of letters randomly displayed on a liquid crystal screen. To minimize learning effects, subjects will be pre-trained to a competence plateau using a software application to be developed for this project. This proposal also includes effort from Drs. Richard Moon, and Richard Vann.

Terrence Allen, MD, Assistant Professor in the Division of Women’s Anesthesia & Critical Care Medicine was awarded a two-year $45,341 Society for Obstetric Anesthesia and Perinatology 2012 Gertie Marx Education & Research Grant entitled “Mechanisms of Progesterone mediated effect on cytokine induced Metalloproteinase activity in human trophoblast cells”. Preterm delivery (PTD) and preterm premature rupture of membranes (PPROM) are major problems in the United States and internationally. The mechanisms resulting in PPROM are not well understood. Recent evidence from work under Dr. Amy Murtha in the Department of Obstetrics and Gynecology at Duke University has clearly demonstrated that woman with PPROM have global thinning of the chorion layer of the fetal membranes even at sites remote from membrane rupture when compared to term and preterm patient. It is likely that inflammatory cytokines and matrix metalloproteinases (MMPs) are involved in this significant tissue remodelling. Recently the FDA has approved the use of 17 hydroxyprogesterone caproate injections (17- OHP) to reduce the risk of PTD before 37 weeks in women with a previous history of at least one spontaneous PTD. The mechanisms by which 17- OHP and other progestins provides protection remains unclear. Recent work demonstrates that progesterone protects cytotrophoblast cell death induced by oxidative stress and that this effect is likely mediated through PGRMC1. Furthermore, research has also shown that progesterone decrease the MMP9 activity induced by TNF in cultured human fetal membrane. This project will focus on determining the role of PGRMC1 in progesterone’s modulation of MMP 9 activity using a human trophoblastic cell line which produces PGRMC1 and lacks the nuclear progesterone receptor (HTR8/SVneo cells) and cultured human fetal membranes.

Ashraf Habib, MD was awarded the SAMBA 2011 Outcomes Research Award in the amount of $100.000 for the proposal entitled “Identification of predictors for severe acute pain and persistent pain after breast surgery”. The goal of these grants is to further scientific inquiry and clinical knowledge in the field of Ambulatory Anesthesia. The largest grant, for $100,000 ($50,000 per year for 2 years) is intended to address a significant issue in Ambulatory Anesthesia.